Abnormal uptake and release of Ca2+ ions from human malignant hyperthermia-susceptible sarcoplasmic reticulum.

Malignant hyperthermia (MH) is a pharmacogenetic myopathy that occurs in humans and several other mammalian species. There has been limited investigation of Ca2+ transport by human heavy sarcoplasmic reticulum (HSR) vesicles despite the fact that mutations of the ryanodine receptor Ca2+ release channel have been linked to inheritance of MH. In this study, the Ca2+ release and uptake mechanisms in human MH-susceptible HSR (MHS) vesicles were investigated and the kinetics and sensitivity compared to normal vesicles. Alterations in Ca2+ regulation were thereby elucidated. HSR vesicles from 6 normal (MHN) and 5 MHS patients were compared using a dual-wavelength continuous Ca2+ flux assay in the presence of pyrophosphate. The loading capacity and loading rate of Ca2+ in MHS vesicles were reduced by almost 50%. These parameters were restored to normal when the Ca2+ channel blocker ruthenium red was added. Calcium-induced calcium release, halothane-induced calcium release, and trifluoperazine-induced calcium release were clearly elevated in MHS HSR vesicles compared to MHN vesicles. The results suggest that MH ryanodine receptors exist in a more open resting state than those in normal muscle.